Recording seizures from within the brain

Get out your tin foil hat: newer deep brain stimulation devices allow doctors to record seizures over many months

Regrouping on fragile X drug strategies

Several clinical trials for people with fragile X syndrome didn't meet organizers' goals. The field is regrouping.

Potential HIV drugs hit three targets at once

News from the American Chemical Society meeting in Denver

Cancer

Who regulates the regulators? Drosha

MicroRNAs have emerged as important master regulators in cells, since each one can shut down several target genes. Riding on top of the master regulators is Drosha, the RNA-cutting enzyme that initiates microRNA processing in the nucleus. Drosha and its relative Dicer have been attracting attention in cancer biology, because they are thought to be behind a phenomenon where cancerous cells can “infect” their healthy neighbors via tiny membrane-clothed packets called exosomes.

At Emory, pharmacologist Zixu Mao and colleagues recently published in Molecular Cell their findings that Drosha is regulated by stress (experimentally: heat or peroxide) through p38 MAP kinase.

Although we mention relevance to cancer above, this is one of those basic cell biology findings that may have applicability to several areas of medicine. Alterations in miRNA processing have been linked to neurodegenerative disease (Fragile X-associated tremor/ataxia syndrome, for one example). MicroRNA-packed exosomes are also being studied by biomedical engineers as potential therapeutic tools in regenerative medicine, so knowing what cellular stress does to miRNA production could be useful. Read more

Posted on by Quinn Eastman in Cancer, Heart, Neuro Leave a comment

BAI1: a very multifunctional protein

Everything is connected, especially in the brain. A protein called BAI1 involved in limiting the growth of brain tumors is also critical for spatial learning and memory, researchers have discovered.

Mice missing BAI1 have trouble learning and remembering where they have been. Because of the loss of BAI1, their neurons have changes in how they respond to electrical stimulation, and subtle alterations in parts of the cell needed for information processing.

The findings may have implications for developing treatments for neurological diseases, because BAI1 is part of a protein regulatory network neuroscientists think is connected with autism spectrum disorders.

The results were published online March 9 in Journal of Clinical Investigation.

Erwin Van Meir, PhD, and his colleagues at Winship Cancer Institute of Emory University have been studying BAI1 (brain-specific angiogenesis inhibitor 1) for several years. Part of the BAI1 protein can stop the growth of new blood vessels, which growing cancers need. Normally highly active in the brain, the BAI1 gene is lost or silenced in brain tumors, suggesting that it acts as a tumor suppressor.

The researchers were surprised to find that the brains of mice lacking the BAI1 gene looked normal anatomically. They didn’t develop tumors any faster than normal, and they didn’t have any alterations in their blood vessels, which the researchers had anticipated based on BAI1’s role in regulating blood vessel growth. What they did have was problems with spatial memory.

Read more

Posted on by Quinn Eastman in Cancer, Neuro Leave a comment

Explainer: oncolytic viruses

A recent publication from Bill Kaiser’s and Ed Mocarski’s labs in Cell Host & Microbe touches on a concept that needs explaining: oncolytic viruses.

Viruses have been subverting the machinery of healthy cells for millions of years, and many viruses tend to infect particular tissues or cell types. So they are a natural starting point for researchers to engineer oncolytic viruses, which preferentially infect and kill cancer cells.

Several oncolytic viruses have progressed to advanced clinical trials. Amgen’s “T-Vec”, a modified herpes simplex virus, could be the first to be approved by the FDA this year based on its efficacy against metastatic melanoma.  Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Nox4 inhibitor expands its reach to A-T

Emory dermatologist Jack Arbiser has been investigating (and recently patented) inhibitors of the enzyme Nox4 as potential anti-cancer drugs.

Nox4 has emerged as a potential therapeutic target in ataxia-telangiectasia, a rare multifaceted genetic disorder that leads to neurological problems, a weakened immune system and an increased risk of cancer. Ataxia-telangiectasia (or A-T) is caused by a defect in ATM, a sensor responsible for managing cells’ responses to DNA damage and other kinds of stress.

In a February PNAS paper, researchers at the National Cancer Institute led by William Bonner report that a Nox4 inhibitor can dial back oxidative stress and DNA damage in ataxia-telangiectasia cells, and can reduce cancer rates in a mouse model of the disease. Nox4 was activated in cells and tissue samples obtained from A-T patients.

The Nox4 inhibitor the NCI team used, fulvene-5, was originally identified by Arbiser in a 2009 Journal of Clinical Investigation paper as a possible treatment for hemangiomas, a common tumor in infants that emerges from blood vessels.

David Lambeth, an expert on the NADPH oxidase family of enzymes, and his team recently described Nox4 as an “hydrogen peroxide-generating oxygen sensor.”

 

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No junk: long RNA mimics DNA, restrains hormone responses

It arises from what scientists previously described as “junk DNA” or “the dark matter of the genome,” but this gene is definitely not junk. The gene Gas5 acts as a brake on steroid hormone receptors, making it a key player in diseases such as hormone-sensitive prostate and breast cancer.

Unlike many genes scientists are familiar with, Gas5 does not encode a protein. It gets transcribed into RNA, like many other genes, but with Gas5 the RNA is what’s important, not the protein. The RNA accumulates in cells subjected to stress and soaks up steroid hormone receptors, preventing them from binding DNA and turning genes on and off.

Emory researchers have obtained a detailed picture of how the Gas5 RNA interacts with steroid hormone receptors. Their findings show how the Gas5 RNA takes the place of DNA, and give hints as to how it evolved.

The results were published Friday in Nature Communications.

Scientists used to think that much of the genome was “fly-over country”: not encoding any protein and not even accessed much by the cell’s gene-reading machinery. Recent studies have revealed that a large part of the genome is copied into lincRNAs (long intergenic noncoding RNAs), of which Gas5 is an example. Read more

Posted on by Quinn Eastman in Cancer, Immunology Leave a comment

Rules of thumb for drug discovery

People interested in drug discovery may have heard of “Lipinski’s rule of five,” a rough-and-ready set of rules for determining whether a chemical structure is going to be viable as a orally administered drug or not. They basically say that if a compound is too big, too greasy or too complicated, it’s not going to get into the body and make it to the cells you want to affect. These guidelines have been the topic of much debate among medicinal chemists and pharmacologists.

The namesake for this set of rules, Chris Lipinski, will be speaking at Winship Cancer Institute Wednesday afternoon (4:30 pm, Nov 5, C5012) on “The Rule of 5, Public Chemistry-Biology Databases and Their Impact on Chemical Biology and Drug Discovery.” Lipinski spent most of his career at Pfizer (while there, he published the “rule of 5 paper“) and now is a consultant at Melior Discovery.

Posted on by Quinn Eastman in Cancer, Uncategorized Leave a comment

Divide and conquer vs lung cancer

Doctors are using a “divide and conquer” strategy against lung cancer, and in some corners of the battlefield, it’s working. A few mutations – genetic alterations in the tumor that don’t come from the patient’s normal cells — have been found for which drugs are effective in pushing back against the cancer.

However, most lung tumors do not have one of these mutations, and response rates to conventional chemotherapy in patients with advanced lung cancer are poor. Generally, only around 20 percent of patients show a clinical response, in that the cancer retreats noticeably for some time.

Johann Brandes and colleagues at Winship Cancer Institute have been looking for biomarkers that can predict whether an advanced lung tumor is going to respond to one of the most common chemotherapy drug combinations, carboplatin and taxol.

“The availability of a predictive test is desirable since it would allow patients who are unlikely to benefit from this treatment combination to be spared from side effects and to be selected for other, possibly more effective treatments,” Brandes says.

Brandes’ team’s data comes from looking at patients with advanced lung cancer at the Atlanta VAMC from 1999 to 2010. In a 2013 paper in Clinical Cancer Research, the team looked at a protein called CHFR. It controls whether cells can reign in their cycles of cell division while being bombarded with chemotherapy.

In this group being treated with carboplatin and taxol, patients who had tumors that measured low in this protein lived almost four months longer, on average, than those who had tumors that were high (9.9 vs 6.2 months).

His team takes a similar approach in a new paper published in PLOS One. Postdoc Seth Brodie is the first author of the PLOS One paper; he is also co-first author of the CHFR paper along with Rathi Pillai. Read more

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Pilot human trial for image-guided cancer surgery tool

The Spectropen, a hand-held device developed by Emory and Georgia Tech scientists, was designed to help surgeons see the margins of tumors during surgery.

Some of the first results from procedures undertaken with the aid of the Spectropen in human cancer patients were recently published by the journal PLOS One. A related paper discussing image-guided removal of pulmonary nodules was just published in Annals of Thoracic Surgery.

To test the Spectropen, biomedical engineer Shuming Nie and his colleagues have been collaborating with thoracic surgeon Sunil Singhal at the University of Pennsylvania.

As described in the PLOS One paper, five patients with cancer in their lungs or chest participated in a pilot study at Penn. They received an injection of the fluorescent dye indocyanine green (ICG) before surgery.

ICG is already FDA-approved for in vivo diagnostics and now used to assess cardiac and liver function. ICG accumulates in tumors more than normal tissue because tumors have leaky blood vessels and membranes. The Spectropen shines light close to the infrared range on the tumor, causing it to glow because of the fluorescent dye.

[This technique resembles the 5-aminolevulinic acid imaging technique for brain tumor surgery being tested by Costas Hadjipanayis, described in Emory Medicine.]

In one case from the PLOS One article, the imaging procedure had some tangible benefits, allowing the surgeons to detect the spread of cancerous cells when other modes of imaging did not. Read more

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Potential anticancer drugs from humble sources

Jing Chen and colleagues at Winship Cancer Institute recently published a paper in Molecular CellMost of the paper deals with a metabolic enzyme, 6PGD (6-phosphogluconate dehydrogenase), and how it is more active in cancer cells.

Rhubarb_Flower

Rheum palmatum/Chinese rhubarb/da-huang

Tucked in at the end is a note that an inhibitor of 6GPD with an odd name, physcion, has anticancer activity in Chen’s team’s hands. Physcion, also known as parietin, is an orange-yellow pigment extractable from lichens and Chinese rhubarb that has been employed as an anti-mildew agent.

Probing cancer cells’ warped metabolism is a promising approach, for both drug discovery and finding effective ways to combine existing drugs, because of the Warburg effect: cancer cells’ tendency to suck up lots of sugar and use it in energy-inefficient ways. Read more

Posted on by Quinn Eastman in Cancer 1 Comment

Cancer immunotherapy, meet chimera

697px-Chimera_d'arezzo,_fi,_03

In Greek mythology, the chimera was a monstrous fire-breathing creature composed of the parts of three animals: a lion, a snake and a goat.

Adoptive cell transfer is advancing as a cancer immunotherapy technique. It involves removing some of a patient’s immune cells, culturing them in the laboratory, and then infusing the cells back into the patient. The idea is to enhance the ability of the immune cells to attack the tumors far beyond what the immune system was able of doing on its own.

Two promising examples are the National Cancer Institute’s approach of treating advanced melanoma with IL-2-stimulated immune cells, and several investigators’ approach of genetically engineering T cells to attack leukemias or lymphomas.

Jacques Galipeau and colleagues at Winship Cancer Institute have developed a chimeric molecule for stimulating immune cells, which appears to have unique powers beyond simply the sum of its two parts. The molecule is called GIFT4, a fusion of the immune signaling molecules GM-CSF (often used in cancer treatment) and IL-4.

Read more

Posted on by Quinn Eastman in Cancer, Immunology Leave a comment
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